Perspective: Microbicides Come of Age?
By Robin J. Shattock, Ph.D.*
Growing up can be a painful business, especially when the optimism of youth is tempered by the reality of experience.
Microbicides, often seen as the lesser sibling of vaccines, therapeutics and safe sex promotion, are finally coming of age: six products are currently moving into large Phase III trials with a pipeline full of new candidates following close behind. What should this field learn from its older relatives, and how best can microbicides be embraced as an ally in the fight against AIDS? The next few years will be critical in seeing how the family dynamics play out. The promise of microbicides is that they could be available within a far shorter timescale than an effective vaccine or wide-scale treatment. But how realistic is such tantalizing promise, and what hurdles exist to realizing early gains in HIV prevention?
Microbicides, vaginal formulations designed to prevent transmission of sexually transmitted infections (STIs), and more recently specifically HIV, are by no means a new idea. Topical agents from lemon juice to soap have been applied by women for generations in an attempt to counter STIs. But early hopes that simple agents capable of destroying viral particles would provide a rapid solution to the HIV problem were dashed when it was observed that the surfactant candidate nonoxynol-9 not only failed to prevent infection but increased susceptibility amongst frequent users of the product. Experience has taught that, above all else, microbicides must not disturb natural physical barriers to infection. Thus, as with vaccines, the microbicide field has had to accept that HIV protection may be more complex than first thought.
Meanwhile, in the early 80s several independent groups started work on developing polyanion-based microbicides that, instead of destroying viral particles, interfere with processes of viral attachment and fusion with target cells. Starved of funding in a climate that expected imminent development of an effective vaccine, progress was only sustained by a small but dedicated field of researchers and supportive project officers. This important but un-coordinated effort led to parallel development of similar products. More recent acceptance that an effective vaccine was still far from being realized, that safe-sex promotion was failing to halt the epidemic and that treatment for all might not be attained any time soon, has led to a surge in microbicide funding. The net result: five products with similar modes of action (polyanions) and one surfactant based product (SAVVY) all entering Phase III clinical trails. Whether agreement with the rationale for taking all six products into large-scale efficacy trials is a “majority” or “minority” viewpoint depends on who you talk to. While funders grapple with conflicting allegiances and intended trial sites stand vacant, many scientist struggle with the scientific rationale for such an approach (1), noting uncomfortable parallels with the vaccine field (2).
In contrast, rapid developments in understanding the mechanisms of HIV transmission is bringing a new appreciation to both vaccine and microbicide development. The large number of different cellular receptors involved in establishing HIV infection and the rapid kinetics of viral dissemination within an infected individual suggest that no single approach may be effective (3). While for vaccines this may mean harnessing innate, cellular and humoral arms of the immune response, for microbicides it may mean targeting alternative and/or sequential pathways involved in mucosal infection and rapid dissemination to draining lymph nodes; in particular viral attachment, fusion and proviral formation (4). Time and distribution of viral exposure present further challenges for any intervention strategy; HIV infection of susceptible cells within mucosal tissue can occur within minutes, while dendritic cell uptake of the virus may maintain its infectivity in mucosal tissue for several days. For vaccines this may mean that sufficiently high levels of specific effector cells (B and T cells) may have to be maintained in order to prevent infection. For microbicides it means that compounds targeted against infectious virions and/or infected cells must be adequately distributed within the genital tract at concentrations sufficient to neutralize or inactivate virus within minutes. In contrast, compounds (e.g., chemokine antagonists, fusion inhibitors, or reverse transcriptase [RT] inhibitors) targeted against susceptible cells must be able to reach their specific targets (e.g., dendritic cells, macrophages, and T cells) at least as well as the infectious virus and may need to be present for prolonged periods. Thus it is highly likely that a combination of such approaches may be required for an effective HIV microbicide. While some combinations may demonstrate synergistic anti-HIV activity, others may be required to provide simultaneous blockade of multiple transmission pathways. In this respect microbicides could learn from its other older sibling, HIV therapeutics, where combinations are critical for viral control. Furthermore, resistance to some microbicide candidates may also occur if used by women unaware of their HIV status. The likely use of RT inhibitors (e.g., nucleoside inhibitor PMPA and non-nucleoside inhibitors like TMC120 and UC781) as microbicide candidates means this lesson may have particular relevance to both fields (microbicides and treatment) since resistance induced by either approach would compromise the efficacy of the other.
Clearly there is a strong scientific rationale for rapid development of combination microbicides and such an approach will ultimately provide the best chance for demonstrating efficacy in clinical trials. So what are the hurdles to rapidly moving combinations into efficacy trials? The first derives from a reluctance to share intellectual property rights, or a desire to demonstrate efficacy for “own” or “owned” agents before considering combinations. Yet the whole objective of microbicides—to provide cheap, affordable protection—doesn’t equate with large profits. Pharmaceutical companies need to join the field, not with an eye to the bottom line (5) but for the possible PR value: not an impossible dream when you see the landmark agreement signed between Tibotec (a subsidiary of Johnson and Johnson) and the International Partnership for Microbicides (6). Other constraints include a less than clear pathway to regulatory approval, although approval of an effective combination may ultimately be easier than for a merely partially effective single agent. But perhaps the biggest hurdle to rapid combination development is the sequential nature of clinical trials. While the current planned Phase III trials may have gone beyond the point of no return, it would seem almost reckless to persist in a pattern of linear, sequential design of single-agent trials of products with similar activity when combination products can be justified, conceptualized, and tested now. For effective microbicides to be realized in a meaningful timescale, the field as a whole and funders in particular need to be able to prioritize candidate and combination selection and provide a fast track into clinical efficacy trials. Such vision and co-ordination has yet to emerge.
There is another promising relationship that to date has been unexplored: the potential synergy between vaccines and microbicides. Traditionally this has been discussed in terms of shared trial sites, placebo arms and trial infrastructure. It is unclear whether a true synergy of effort can take place by performing different prevention trials in the same sites or whether possible crossover between study participants would obscure data analysis and/or saturate recruitment capacity. However, an alternative synergy between these fields may also exist. A partially-effective microbicide might show significant synergy with a partially-effective vaccine, the former significantly lowering the viral challenge with which any vaccine-induced immune response needs to contend. Furthermore, protective immunity to HIV is likely to require prolonged raised mucosal immune responses, yet such responses are typically short-lived. Although controversial, some have suggested that studies in cohorts of highly-exposed persistently seronegative (HEPS) women means that repeated vaginal exposure to antigen may be required to maintain resistance to infection. Microbicides could be used to deliver relevant HIV vaccine antigens recurrently, maintaining mucosal immunity induced by conventional vaccine approaches. Likewise, any resultant enhancement of mucosal immunity would augment microbicide efficacy where there was suboptimal compliance. Although such synergy is at present mere conjecture, the potential benefits warrant further investigation.
Finally microbicides could also learn from one other older sibling, the field of safe-sex promotion. Despite renewed emphasis on “ABC” programs (abstinence, be faithful or condomize), this strategy is clearly failing women for it implies they always have a choice. The sad reality for most women at risk is that they often cannot choose abstinence, that faithfulness only works when adopted by both partners, and that condom use is predominantly controlled by men. This is all the more pertinent in stable relationships where condom use becomes an issue of trust and the fear of being barren is worse than that of becoming infected with HIV (7). Ultimately the success of “ABC” is determined by the actions of men. Microbicides, in contrast, are aimed at empowering women since they may be applied covertly without their partner’s knowledge. Yet too much emphasis on their covert use could have a negative impact. By implying a level of suspicion about a partner’s faithfulness, women may be afraid to use such products for fear of being found out: and if the product is easy to disguise, there are still the applicators to hide. There is also the issue of timing – appropriate application of a microbicide would require a degree of anticipation that is often not available to many women. So microbicides are mostly likely to succeed if they have both sustained activity, allowing them to be applied hours (perhaps days) before intercourse, and if they have male approval. But male approval could also have negative connotations if introduction of a partially-effective microbicide led to migration away from condom use. While this specter has often been raised, recent modelling has predicted that for a microbicide with only 50% efficacy to have a detrimental impact on transmission rates, condom use would have to be higher than 80% (8).
So how might the future play out? If lessons from the past are ignored, the future might look something like this: Lack of prioritization and insufficient funding (currently still a fraction of the budget for other prevention measures) means effective microbicides are not developed for a decade or more. Clinical trials again demonstrate little to no efficacy and/or adverse effects. Developing countries and potential donors become less willing to support microbicide efficacy trials (the same might also be true with repeated vaccine failures). Competition for sites with the vaccine field means that trials become harder to perform. Early introduction of partially effective microbicides leads to decreased condom use and even antiretroviral resistance.
However, if the field has the vision to learn from previous experience, a very different future might be realized: Rational prioritization of candidates and combinations provides a fast track into human efficacy trials. First generation products show detectable and significant efficacy (>30%), second generation products, most likely combinations, demonstrate increased efficacy (>70%). Subsequent introduction of sustained release formulations improve subject compliance leading to increased gains in efficacy. Joint condom and microbicide promotion a success; some reduction in condom use, but benefits of microbicide use in unprotected sex acts leads to reduction in transmission rates. Microbicides demonstrate potent synergy with partially-effective vaccines and/or are formulated to maintain mucosal immunity. Finally, microbicides are strategically marketed so that they become a desirable commodity, creating a sustained demand for product and ongoing use.
It is easy for a young field to be full of promise, but growing up means being able to deliver. The future that microbicides deliver may be as dependent upon the ability to profit from the past as it is on a clear decision path for the future.
1. Gross M, Am. J. Public Health 94, 1085 (2004). PubMed
2. Burton DR, et al., Science 303, 316 (2004). PubMed
3. Miller CJ, Shattock RJ, Microbes Infect. 5, 59 (2003). PubMed
4. Shattock RJ, Moore JP, Nat. Rev. Microbiol. 1, 25 (2003). PubMed
5. Moore JP, Shattock RJ, J. Antimicrob. Chemother. 52, 890 (2003). PubMed
6. International Partnership for Microbicides (IPM). Press release: 29 March 2004. Available online
7. Shattock R, Solomon S, Lancet 363, 1002 (2004). PubMed
8. Foss AM, et al., AIDS 17, 1227 (1991). PubMed
*Robin J. Shattock is in the Department of Cellular and Molecular Medicine: Infectious Diseases, St George’s Hospital Medical School, London, UK.